Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
The United States and other countries around the world are experiencing a demographic sea change owing to the rapidly growing elderly and ‘Baby Boomer’ populations (Trojanowski, (2008) Neurosignals 16: 5-10). Our astonishing biomedical advances in the last half-century have greatly increased our life expectancy. But as a consequence of living longer, our population now faces an increase in the incidence of neurodegenerative diseases. These truly disastrous disorders include Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis (ALS) and the frontal temporal dementias (Forman et al. (2004) Nat. Med. 10:1055-1063).
In the future, personalized genome sequencing will become routine, empowering us to define the genetic basis of many human diseases. Currently, however, complete genome sequencing for individuals to discover rare pathogenic mutations is still too costly and time consuming. Thus, more creative approaches are needed for disease gene discovery; moreover, even once genes are revealed, the need for innovative approaches to elucidate causality remains critical.
ALS, also known as Lou Gehrig's disease, is a devastating adult-onset neurodegenerative disease that attacks upper and lower motor neurons (Cleveland and Rothstein, 2001). A progressive and ultimately fatal muscle paralysis ensues, usually causing death within 2 to 5 years of disease onset. ALS is mostly sporadic, but approximately 10% of cases are familial. Pathogenic mutations in several genes have been linked to familial and sporadic ALS, including SOD1, TARDBP, FUS/TLS, VAPB, OPTN and others (Van Damme and Robberecht, 2009). Two of these genes, TARDBP (which encodes TDP-43) and FUS/TLS (FUS) are notable because they encode related RNA-binding proteins (Lagier-Tourenne and Cleveland, 2009). Moreover, both of these proteins have been identified as components of pathological inclusions in neurons of ALS patients (Kwiatkowski et al., 2009; Neumann et al., 2006; Vance et al., 2009). Indeed, an emerging concept suggested by the association of FUS and TDP-43 to ALS is that defects in RNA metabolism might contribute to disease pathogenesis. Accordingly, genes encoding proteins involved in RNA metabolism may provide a new avenue to pursue in the development of efficacious therapeutic targets useful for the treatment of these devastating neurological disorders.